FRONT LINE COVID-19 CRITICAL CARE ALLIANCE

PREVENTION & TREATMENT PROTOCOLS FOR COVID-19

I-RECOVER
Management Protocol for Long Haul COVID-19 Syndrome (LHCS)
The approach outlined below is a consensus protocol based on a collaboration led by Dr. Mobeen Syed (“Dr. Been”), Dr. Ram Yogendra,
Dr. Bruce Patterson, Dr. Tina Peers, and the FLCCC Alliance. Given the lack of clinical treatment trials of Long Haul COVID-19 Syn-
drome, these recommendations are based on the pathophysiologic mechanisms of COVID-19 and post-viral illnesses along with our
collective experience observing profound and sustained clinical responses achieved with the treatment approaches below.
This protocol has also been used to treat post-vaccine inflammatory syndromes with similar success. As with all FLCCC Alliance ­protocols,
the components, doses, and durations will evolve as more clinical data accumulates. For the most up-to-date information on optional
treatments, go to: flccc.net/flccc-protocols-a-guide-to-the-management-of-covid-19 (see LHCS section).

Initial therapy of If presenting with neurologic If presenting with shortness of

Long Haul COVID-19 Syndrome: symptoms, i.e. poor concentration, breath or low oxygen levels:
forgetfulness, mood disturbance:
IVERMECTIN FLUVOXAMINE PULMONARY EVALUATION
0.2–0.4 mg/kg dose – once daily with meals* for 3–5 days 50 mg – twice daily for 15 days. Refer to lung specialist if available,
(higher doses are sometimes needed in anosmia). Reduce dose or discontinue if side otherwise perform chest imaging (CT
* Take on empty stomach if presenting with nausea/diarrhea/anorexia. effects develop. Doses as low as 9 mg preferred) to assess for second­­ary
twice daily have shown ­efficacy. organizing Pneumonia (OP).
After 3–5 days, change to once or twice weekly depending
on the time to symptom recurrence/persistence. Monitor closely as some patients may If findings consistent with second­­ary
respond poorly. Some individuals can OP found, initiate Corticosteroid
Discontinue after 2–4 weeks if all symptoms have resolved Therapy as below. May need to
and do not recur. experience acute anxiety; monitor
and treat carefully to prevent rare repeat or prolong course of treat­
Relative Contraindications: escalation to suicidal or violent ment if symptoms or oxygen needs
– Patients on Warfarin require close monitoring and dose adjustment.
behavior. persist.
– Pregnant or lactating women require a more in-depth risk/benefit
assessment.
CT computed tomography scan
OP organizing pneumonia

If not all symptoms If symptoms still unresolved or recur after

resolve with ivermectin: ivermectin and corticosteroid regimens:
CORTICOSTEROID THERAPY TREATMENT OF SUSPECTED MAST CELL ACTIVATION
A tapering dose of prednisone as follows: Choose a Type I and a Type II antihistamine along with a mast cell stabilizer –
1. 0.5 mg/kg daily for 5 days for example, Loratadine, Famotidine, and Rupatadine. Change medicines if
2. 0.25 mg/kg daily for 5 days poor response. United States FDA approved doses of many of the below medi-
3. 0.12 mg/kg daily for 5 days cines are once daily but can use up to three times daily with caution and close
monitoring if poor response or side effects.
Take in morning to lessen impact on sleep.
Side effects may include: Increased appetite, mood changes, insomnia, First-line Therapy
raised blood glucose, dyspepsia. Low histamine diet
Type l antihistamines: Loratadine 10 mg, or Cetirizine 10 mg, or Fexofenadine
180 mg – three times daily as tolerated.
Type ll antihistamines: Famotidine 20 mg, or Nizatidine 150 mg – twice daily
For use in all patients: as tolerated.
MACROPHAGE/MONOCYTE REPOLARIZATION THERAPY Mast cells stabilizers:
– Rupatadine 10 mg – once daily, or Ketotifen 1 mg – once daily at night
Vitamin C — 500 mg twice daily (increase as tolerated).
Omega-3 Fatty Acids — 4 gm/daily (Vascepa, Lovaza, or – May add: Sodium Cromoglycate 200 mg – three times daily (increase
DHA/EPA) slowly), or Quercetin 500 mg – three times daily.
Atorvastatin — 40 mg daily Second-line Therapy
Melatonin — 2–10 mg nightly, start with low dose, Montelukast 10 mg (beware depression in some) – once daily.
increase as tolerated in absence of sleep disturbance. Low Dose Naltrexone (LDN) – start with 0.5 mg daily, increasing by 0.5 mg
weekly up to 4.5 mg daily. Avoid if on opiates.
Additional Supplement Diazepam 0.5–1 mg twice daily.
Vitamin D3 — 2,000–4,000 IU daily SSRIs.

DHA Docosahexaenoic acid IU international units

EPA eicosapentaenoic acid mg/kg dose in mg per kg body weight

For updates and more information on the treatment protocols of the FLCCC Alliance please see: flccc.net     I-RECOVER · Version 1 · June 16, 2021 · Page 1/3
 FRONT LINE COVID-19 CRITICAL CARE ALLIANCE
PREVENTION & TREATMENT PROTOCOLS FOR COVID-19
I-RECOVER
Management Protocol for Long Haul COVID-19 Syndrome (LHCS)
The Long Haul COVID-19 Syndrome (also “Post-COVID-19 Syndrome”)
Excerpt from the “Guide to the Management of COVID-19“ by Dr. Paul Marik / FLCCC Alliance
flccc.net/flccc-protocols-a-guide-to-the-management-of-covid-19
The Long Haul COVID-19 Syndrome (LHCS) is characterized by pro-
longed malaise, headaches, generalized fatigue, sleep difficulties,
hair loss, smell disorder, decreased appetite, painful joints, dyspnea,
chest pain and cognitive dysfunction [400-411] Up to 80% of patients
experience prolonged illness after COVID-19. LHCS is not only seen
after the COVID-19 infection but it is being observed in some people
that have received vaccines (likely due to monocyte activation by the
spike protein from the vaccine). LHCS may persistent for months after
the acute infection and almost half of patients report reduced quality
of life. Patients may suffer prolonged neuropsychological symptoms,
including multiple domains of cognition. [409,412] A puzzling feature
of LHCS is that it is not predicted by initial disease severity; post-CO-
VID-19 frequently affects mild-to-moderate cases and younger adults
that did not require respiratory support or intensive care. [411] The
symptom set of LHCS is in majority of the cases very similar to the
chronic inflammatory response syndrome (CIRS) / myalgic encephalo-
myelitis / chronic fatigue syndrome. [411] An important differentiating
factor from CIRS is the observation that LHCS continues to improve
on its own albeit slowly in majority of the cases. Another important
observation is that LHCS includes more young people compared to
severe COVID-19 that affects older people or persons with comor-
bidities. Furthermore, the similarity between the mast cell activation
syndrome and LHCS has been observed, and many consider post-
COVID-19 to be a variant of the mast cell activation syndrome. [413]
The LHCS syndrome in highly heterogenous and likely results from a
variety of pathogenetic mechanisms Furthermore, it is likely that de-
layed treatment (with ivermectin) in the early symptomatic phase will
results in a high viral load which increase the risk and severity of LHCS.
The following theories have been postulated to explain LHCS: [411]
1. Ongoing respiratory symptoms (SOB, cough, reduced effort toler-
ance) may be related to unresolved organizing pneumonia (acti-
vate pulmonary macrophages).
2. Monocyte activation syndrome. Persistence of viral debris in
monocytes results in an ongoing immune response in an attempt
by the immune system to clear the offending protein(s) and viral
RNA fragments.
3. The neurological symptoms may be related micro- and/or macro-
vascular thrombotic disease which appears to be common in se-
vere COVID-19 disease. [414] Brain MRIs’ 3 months post-infection
demonstrated micro-structural changes in 55% of patients. [415]
In addition, features of encephalopathy may be related to enceph-
alitis and auto-reactive brain antibodies [416] as well as severe
cerebral vasoconstriction. [417] The brain microvasculature ex-
presses ACE-2 receptors and SARS-CoV-2 “pseudovirons” may bind
to the microvascular endothelium causing cerebral microvascular
inflammation and clotting. [418].
For updates and more information on the treatment protocols of the FLCCC Alliance please see: flccc.net     I-RECOVER · Version 1 · June 16, 2021 · Page 2/3
2/3
4. An unmasking of mast cell activation syndrome (MCAS), or trig-
gering of mast cell activation syndrome. Mast cells are present in
the brain, especially in the median eminence of the hypothalamus,
where they are located perivascularly close to nerve endings posi-
tive for corticotrophin releasing hormone. [419] Following stimu-
lation, mast cells release proinflammatory mediators such as his-
tamine, tryptase, chemokines and cytokines which may result in
neurovascular inflammation. [419] The “brain-fog”, cognitive im-
pairment and general fatigue reported in long-COVID-19 may be
due to mast cell related neurovascular inflammation.
Clinical signs and symptoms can be grouped in the following clusters.
The reason for this grouping is to allow organ specific targeted thera-
py/individualized therapy.
1. Respiratory: shortness of breath, congestion, persistent cough, etc.
2. Neurological/psychiatric: brain fog, malaise, tiredness, headaches,
migraines, depression, inability to focus/concentrate, altered cogni-
tion, insomnia, vertigo, panic attacks, tinnitus, anosmia, phantom
smells, etc.
3. Musculoskeletal: myalgias, fatigue, weakness, joint pains, inability
to exercise, post-exertional malaise, inability to perform normal ac-
tivities of daily life (ADL’s).
4. Cardiovascular: Palpitations, arrhythmias, Raynaud like syndrome,
hypotension, and tachycardia on exertion.
5. Autonomic: Postural tachycardia syndrome (POTs), abnormal sweating.
6. GIT disturbance: Anorexia, diarrhea, bloating, vomiting, nausea, etc.
7. Dermatologic: Itching, rashes, dermatographia
8. Mucus membranes: Running nose, sneezing, Burning and itchy eyes.
Approach to Treatment
The treatment approach should be individualized according to the
grouping of clinical signs and symptoms. However, in general, it is
likely that patients who received inadequate antiviral treatment
(ivermectin) during the acute symptomatic phase and inadequate an-
ti-inflammatory/macrophage repolarization therapy (corticosteroids,
statins, omega-3 fatty acids, fluvoxamine, ivermectin, etc) during the
acute phase of COVID-19 are much more likely to develop the Post-
COVID-19 Syndrome. In patients with ongoing respiratory symptoms
chest imaging is suggested (preferably a chest CT scan). Those with
unresolved pulmonary inflammation (organizing pneumonia) should
be treated with a course of corticosteroids (prednisone) and closely
followed. A CRP should be measured, and extended corticosteroids
(titrated to the CRP) offered to these patients. Similar to patients who
have recovered from septic shock, [420] a prolonged (many months)
immune disturbance with elevated pro- and anti-inflammatory cyto-
 FRONT LINE COVID-19 CRITICAL CARE ALLIANCE
PREVENTION & TREATMENT PROTOCOLS FOR COVID-19

I-RECOVER 3/3

Management Protocol for Long Haul COVID-19 Syndrome (LHCS)

kines may contribute to the LHCS. This is likely the consequence of
monocyte activation syndrome and monocyte repolarization therapy
is therefore indicated. In addition, a cytokine panel may allow tar-
geted anti-inflammatory therapy (Maraviroc in patients with high
CCR5 levels). It should be noted that much like omega-3 fatty acids,
corticosteroids have been demonstrated to increase expression of
pro-resolving lipids including Protectin D1 and Resolvin D4. [421] An
unknown number of patients who have recovered from COVID-19
organizing pneumonia will develop pulmonary fibrosis with associ-
ated limitation of activity. Pulmonary function testing demonstrates
a restrictive type pattern with decreased residual volume and DLCO.
[406] These patients should be referred to a pulmonologist with ex-
pertise in pulmonary fibrosis. Anti-fibrotic therapy may have a role
in these patients, [380-383] however additional data is required be-
fore this therapy can be more generally recommended. As discussed
above, the serotonin receptor blocker cyproheptadine may reduce
the risk of pulmonary fibrosis. [256]

References
256. Skurikhin EG, Andreeva TV, Khnelevskaya ES et al. Effect of antiserotonin drug on the de-
velopment of lung fibrosis and blood system reactions after intratracheal administration of
bleomycin. Bull Exp Biol Med 2012; 152:519-23.
380. Seifirad S. Pirfenidone: A novel hypothetical treatment for COVID-19. Medical Hypotheses
2020; 144:11005.
381. Saba A, Vaidya PJ, Chavhan VB et al. Combined pirfenidone, azithromycin and prednisolone
in post-H1N1 ARDS pulmonary firbosis. Sarcoidosis Vasc Diffuse Lung Dis 2018; 35:85-90.
382. Spagnolo P, Balestro E, Aliberti S et al. Pulmonary fibrosis secondary to COVID-19: a call to
arms? Lancet Resp Med 2020; 8:750-752.
383. George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role for
antibibrotic therapy. Lancet Resp Med 2020; 8:807-15.
400. Carfi A, Bernabei R, Landi F. Persistent symptoms in patients after acute COVID-19. JAMA 2020.
401. Prescott HC, Girard TD. Recovery from Severe COVID-19. Leveraging the lessons of survival
from sepsis. JAMA 2020.
402. Greenhalgh T, Knight M, A’Court C et al. Management of post-acute COVID-19 in primary
care. BMJ 2020.
403. Chopra V, Flanders SA, O’Malley M. Sixty-day outcomes among patients hospitalized with
COVID-19. Ann Intern Med 2020.
404. Mandal S, Barnett J, Brill SE et al. ‘Long-COVID’: a cross-sectional study of persisting symp-
toms, biomarker and imaging abnormalities following hospitalization for COVID-19. Tho-
rax 2020.
405. Michelen M, Manoharan L, Elkheir N et al. Characterising long-term COVID-19: a rapid liv-
ing systematic review. medRxiv 2020.
406. Huang C, Huang L, Wang Y et al. 6-month consequences of COVID-19 in patients dis-
charged feom hospital: a cohort study. Lancet 2021.
407. Logue JK, Franko NM, McCulloch DJ et al. Sequelae in adults at 6 months after COVID-19
infection. JAMA Network Open 2021; 4:e210830.
408. Janiri D, Carfi A, Kotzalidis GD et al. Posttraumatic stress disorder in patients after severe
COVID-19 infection. JAMA Psychiatry 2021.
409. Voruz P, Allali G, Benzakour L et al. Long COVID neuropsychological deficits after severe,
moderate or mild infection. medRxiv 2021.
410. Al-Aly Z, Xie Y, Bowe B. High-dimensional characterization of post-acute sequalae of CO-
VID-19. Nature 2021.
411. Yong SJ. Long-haul COVID-19: Putative pathophysiology, risk factors, and treatments. me-
dRxiv 2020.
412. Taquet M, Geddes JR, Husain M et al. 6-month neurological and psychiatric outcomes in
236 379 survivors of COVID-19: a retrospective cohort study using electronic health re-
cords. Lancet Psychiatry 2021.
413. Afrin LB, Weinstock LB, Molderings GJ. COVID-19 hyperinflammation and post-Covid-19
illness may be rooted in mast cell activation syndrome. Int J Infect DIs 2020.
414. Bryce C, Grimes Z, Pujadas E et al. Pathopysiology of SARS-CoV-2: targeting of endothelial
cells renders a complex disease with thrombotic microangiopathy and aberrant immune
response. The Mount Sinai COVID-19 autopsy experience. medRxiv 2020.
415. Lu Y, Li X, Geng D et al. Cerebral micro-structutal changes in COVID-19 patients - An MRI-
based 3-month follow-up study. EClinicalMedicine 2020.
416. Franke C, Ferse C, Kreye J et al. High frequency of cerebrospinal fluid autoantibodies in
COVID-19 patients with neurological symptoms. Brain,Behavior, and Immunity 2021.
417. Sirous R, Taghvaei R, Hellinger JC et al. COVID-19-associated encephalopathy with ful-
minant cerebral vasoconstriction: CT and MRI findings. Radiology Case Reports 2020;
15:2208-12.
418. Magro CM, Mulvey JJ, Laurence J et al. Docked severe acute respiratory syndrome corona-
virus 2 proteins within the cutaneous and subcutaneous microvasculature and their role in
the pathogenesis of severe coronavirus disease 2019. Human Pathology 2020; 106:106-16.
419. Theoharides TT, Cholevas C, Polyzoidis K et al. Long-COVID syndrome-associated brain fog
and chemofog: Luteolin to the rescue. Biofactors 2021; 47:232-41.
420. Riche F. Protracted immune disorders at one year after ICU discharge in patients with sep-
tic shock. Crit Care 2018; 22:42.
421. Andreakos E, Papadaki M, Serhan CN. Dexamethasone, pro-resolving lipid mediators and
resolution of inflammation in COVID-19. Allergy 2020.
422. COVID-19 rapid guideline: managing the long-term effects of COVID-19. www.nice.org.uk/
guidance/ng188 . 2020. National Institute for Health and Care Excellence. 4-26-2021.
423. Sanabria-Mazo JP, Montero-Marin J, Feliu-Soler A et al. Mindfulness-based program plus
amygdala and inusla retraining (MAIR) for the treatment of women with fibromyalgia: A
pilot ramdomized controlled trial. J Clin Med 2020; 9:3246.
424. Theoharides TC. COVID-19, pulmonary mast cells, cytokine storms, and beneficial actions
of luteolin. Biofactors 2020; 46:306-8.
425. Bawazeer MA, Theoharides TC. IL-33 stimulates human mast cell release of CCL5 and CCL2
via MAPK and NF-kB, inhibited by methoxyluteolin. Eur J Pharmacol 2019; 865:172760.
426. Weng Z, Patel AB, Panagiotidou S et al. The novel flavone tetramethoxyluteolin is a potent
inhibitor of human mast cells. J Allergy Clin Immunol 2015; 135:1044-52.
427. Patel AB, Theoharides TC. Methoxyluteolin inhibits neuropeptide-stimulated proinflam-
matory mediator release via mTOR activation from human mast cells. J Pharmacol Exp
Ther 2017; 361:462-71.
428. Calis Z, Mogulkoc R, Baltaci AK. The roles of flavonols/flavonoids in neurodegeneration and
neuroinflammation. Mini Rev Med Chem 2020; 20:1475-88.

Disclaimer
The I-RECOVER protocol is borne of clinical experience only and thus is meant solely for educational purposes to health care providers regarding
potentially beneficial empiric treatment approaches for Long Haul COVID-19 Syndrome. Never disregard professional medical advice because of
something you have read on our website and releases. This is not intended to be a substitute for professional medical advice, diagnosis, or treat-
ment in regards to any patient. Treatment for an individual patient is determined by many factors and thus should rely on the judgement of your
physician or qualified health care provider. Always seek their advice with any questions you may have regarding your medical condition or health.

! Please check our homepage www.flccc.net regularly for updates of our COVID-19 Protocols! – New medications may be added and/or dose
changes to existing medications may be made as further scientific studies emerge!

For updates and more information on the treatment protocols of the FLCCC Alliance please see: flccc.net     I-RECOVER · Version 1 · June 16, 2021 · Page 3/3